P h a s e I I E v a l u a t i o n o f T e m o z o l o m i d e a n d 1 3 - c i s - R e t i n o i c A c i d f o r t h e T r e a t m e n t o f R e c u r r e n t a n d P r o g r e s s i v e M a l i g n a n t G l i o m a : A N o r t h A m e r i c a n B r a i n T u m o r C o n s o r t i u m S t u d y By Kurt A. Jaeckle, Kenneth R. Hess, W.K. Alfred Yung, Harry Greenberg, Howard Fine, David Schi
Intelhut.net2International Journal of Pharmaceutical and Clinical Research 2013; 5(4): 141-144 Antiseptics and Antibiotics Used in Regenerative Endodontics Saveetha Dental College and Hospitals, Saveetha University, Chennai, Tamil Nadu, India Available online: 17th September, 2013 ABSTRACT
Contemporary endodontics and the future of endodontics are based on regenerative strategies. Success of these
regenerative endodontic treatments depends on disinfection of the root canal system. Current research in endodontics
focuses on identifying the optimal methods of disinfection of root canal systems to achieve predictable results in
revascularization therapy. Although the use of sodium hypochlorite for disinfection is mandatory, additional intracanal
medicaments are also required to realize this goal. This article reviews the antiseptics and antibiotics used for achieving
disinfection of root canals for regenerative procedures.
Key words: regenerative endodontics, revascularization, disinfection, sodium hypochlorite, antibiotics, chlorhexidine.
the irrigants and medicaments. This may be likened to the Regenerative endodontic procedures can be defined as Lesion sterilization and tissue repair (LSTR) therapy biologically based procedures designed to replace which employs the use of a combination of antibacterial damaged structures, including dentin and root structures, drugs for the disinfection of pulpal and periradicular as well as cells of the pulp-dentin complex. The objectives of regenerative endodontic procedures are to Antiseptics used for disinfection in regenerative regenerate pulp-like tissue, ideally, the pulp-dentin complex; regenerate damaged coronal dentin, such as following a carious exposure; and regenerate resorbed Hypochloric acid disrupts several vital functions of the root, cervical or apical dentin 1. One of the presently microbial cell, resulting in cell death. NaOCl is viable regenerative procedures is revascularization of the commonly used in concentrations between 0.5% and 6%.
root canal. This is done via a blood clot that is induced by It is a potent antimicrobial agent, killing most bacteria over-instrumentation of the root canal system. The instantly on direct contact. It also effectively dissolves revascularization treatment is the disinfection of the root components of dentin. Hypochlorite is the only root canal canal space 2. This article reviews the various agents used irrigant of those in general use that dissolves necrotic and for root canal disinfection during revascularization vital organic tissue. In some articles hypochlorite is treatment, along with a review of literature assessing reported to kill the target microorganisms in seconds, even at low concentrations, although other reports have Need for disinfection during revascularization published considerably longer times for the killing of the The rationale of revascularization is that if a sterile tissue same species. It has been shown that 0.5% or 5% NaOCl, matrix is provided in which new cells can grow, pulp with or without EDTA for irrigation, resulted in vitality can be reestablished. Revascularization protocols considerable reduction of bacterial counts in the canal are derived from the observations of reimplanted and when compared with irrigation with saline 4. This is in auto- transplanted teeth in experimental animals in which accordance with several published reports on the necrotic pulp, devoid of infection, provide a matrix into antibacterial activity of sodium hypochlorite in vitro.
which the cells from the periradicular region could grow Hypochlorite is also the only irrigant capable of brining about destruction of root canal biofilms 5-7.
This sterile matrix that is created is the key to success of In vivo, the antimicrobial effectiveness of NaOCl is treatment. One area wherein maximum research is being limited. The poorer in vivo performance compared with carried out in the field of revascularization is the different in vitro is probably caused by problems in penetration to antimicrobial agents used as intracanal medicaments to the most peripheral parts of the root-canal system such as bring about the disinfection. Since almost no fins, anastomoses, apical canal and lateral canals. Also, instrumentation is carried out (in contrast to routine root the presence of inactivating substances such as exudate canal treatment where disinfection is brought about by from the periapical area, pulp tissue, dentin collagen, and the action of instruments synergistically with irrigants), microbial biofilms counteract the effectiveness of NaOCl the disinfection protocol relies on the chemical actions of 8. Long term exposure of dentin to a high concentration of *Author for correspondence: E-mail: email@example.com Nabeel Ahmed, Prasanna Neelakantan / Antiseptics and Antibiotics… sodium hypochlorite can have a detrimental effect on the antibacterial agent in revascularization treatment, dentin elasticity and flexural strength, based on some in resulted on continued root development at the end of 24 vitro studies 9,10. Considering this limited antibacterial months 18. Also, in contrast to calcium hydroxide, CHX activity in lieu of the anatomical complexities of the root did not cause obliteration of the root canal space by canal space, intracanal medicaments are used for calcification. The root development was also reported to antimicrobial action. However, the use of sodium be faster than when other materials were used for root hypochlorite in endodontics in general and in revascularization treatment, in particular is to be Root canal infections are polymicrobial, consisting of both aerobic and anaerobic bacteria. Because of the Regenerative dental procedures have a long history, complexity of the root canal infection, it is unlikely that originating around 1952, when Dr. B. W. Hermann any single antibiotic could result in effective sterilization reported on the application of calcium hydroxide in a case of the canal. A combination would be needed to address report of vital pulp amputation. Calcium hydroxide has the diverse flora encountered. The most commonly used been used commonly as an intracanal medicament. This medicament is a combination of three antibiotics, referred is mainly due to its high alkaline pH (about 11.5 - 12), to as a triple antibiotic paste (TAP). This formulation was which results in its antibacterial action. The disinfecting first used by Sato et al. and contains metronidazole, action of calcium hydroxide is effective for at least for ciprofloxacin, and minocycline. This combination is one week and the effect drastically reduces thereafter 11.
commercially available as 3-MIX MP 19.
Furthermore, calcium hydroxide has three important Metronidazole is a nitroimidazole compound. It is disadvantages: it is ineffective against Enterococcus selectively toxic to anaerobic microbes. It also exhibits fecalis which is the predominant microbe isolated in broad spectrum antimicrobial activity against against failed root canal treatment 12; it is known to weaken the protozoa and anaerobic bacteria. The presence of certain root structure 13 and, complete removal of the material is redox proteins reduces the nitro group of this compound extremely difficult if not impossible 14. Of these and generates free radicals that enter the cell and induce disadvantages, a point of concern in regenerative DNA damage. This results in rapid cell death 20.
strategies is the potential weakening of tooth structure by this material. Revascularization strategies are employed minocycline are primarily bacteriostatic, inhibiting in immature teeth with open apices, and these teeth protein synthesis by binding to 30S ribosomes in inherently have thin dentinal walls that are predisposed to susceptible organisms. They exhibit broad spectrum of activity against gram positive and gram negative It was also shown by Banchs and Trope that the stem cells at the periradicular region following differentiation derivative of tetracycline with a similar spectrum of result in continued root formation. These cells also help antibacterial activity. Tetracycline inhibits collagenases in res-establishing the vascularity of the pulp. Calcium and matrix metalloproteinases,and is not cytotoxic. It also hydroxide is cytotoxic to the cells of any viable pulp tissue and the stem cells from the apical papilla. This inflammatory cytokine 21, 22. Ciprofloxacin is a synthetic would be detrimental to the revascularization process 15.
floroquinolone with rapid bactericidal action. It inhibits the enzyme bacterial DNA gyrase, which nicks the A recent report showed the efficacy of a 2% double stranded DNA, introduces negative supercoil and chlorhexidine gel in the revascularization treatment.
then reseals the nicked end. The bactericidal action Chlorhexidine (CHX) has antimicrobial properties and probably results from digestion of DNA by exonucleases low cytotoxicity. It is also effective against most whose production is signaled by the damaged DNA. It endodontic pathogens. CHX permeates the microbial cell exhibits very potent activity against gram negative wall or outer membrane and attacks the bacterial bacteria but very limited activity against gram positive cytoplasmic or inner membrane or the yeast plasma bacteria. Most of the anaerobic bacteria are resistant to membrane. In high concentrations, CHX causes ciprofloxacin. Hence it is often combined with coagulation of intracellular components 16. Removal of the material is easy and the most importantly, the material Metronidazole and ciprofloxacin can generate fibroblasts, exhibits substantivity ie., the antibacterial action is long- all of which will enhance success of the regenerative procedure 21-23. It has also demonstrated that while each Chlorhexidine is also a matrix metalloproteinase inhibitor of these antibiotics did not result in complete bacterial 17. MMPs have been shown to be agents of tissue destruction and markers of inflammation. However, similar to other endodontic disinfecting agents, the Hoshino et al. recommended a ratio of 1:1:1 of activity of CHX depends on the pH and is also greatly metronidazole (500 mg), minocycline (100 mg) and reduced in the presence of organic matter.
ciprofloxacin (200 mg) for the 3Mix formulation. The Chlorhexidine may be a safe alternative if this medication carrier or vehicle recommended was propylene glycol, in came into contact with periapical tissues in immature the ratio 1:1, with polyethylene glycol or macrogol. This teeth. CHX, in a clinical study showed that, when used as combination is termed MP 23. The standard recommended IJPCR, October-December, 2013, Vol 5, Issue 4, 141-144 Nabeel Ahmed, Prasanna Neelakantan / Antiseptics and Antibiotics… mix contains 1 part of MP mixed with 7 parts of 3Mix.
Murray PE, Garcia-Godoy F, Hargreaves KM.
This formulation was modified by Takushige et al., who Regenerative endodontics: A review of current status recommended mixing the antibiotics is a formulation of and a call for action.J Endod 2007; 33 (4):377–390.
3:3:1, wherein 3 parts of metronidazole and 3 parts of Jung IY, Lee SJ, Hargreaves KM. Biologically based minocycline are mixed with 1 part of ciprofloxacin. This treatment of immature permanent teeth with pulpal can be mixed with MP or root canal sealers. However, the necrosis: a case series. J Endod 2008; 34 (7), 876– mixture with sealers is presently not recommended 24.
Comparing TAP, calcium hydroxide, and formocresol as Hoshino E, Takushige T. LSTR 3Mix-MP method- intracanal medicaments in non-vital young permanent better and efficient clinical procedures of lesion tooth, the triple antibiotic group showed the highest sterilization and tissue repair (LSTR) therapy. Dent percentage increase in the dentin wall thickness compared with the other two groups 25. It was also reported that Bystrom A, Sundqvist G. Bacteriologic evaluation of TAP can help promote functional development of the the effect of 0.5 percent sodium hypochlorite in pulp–dentin complex. TAP contains both bactericidal endodontic therapy. Oral Surg Oral Med Oral Pathol (minocycline) agents and hence may be considered the Clegg MS, Vertucci FJ, Walker C, et al. The effect of exposure to irrigant solutions on apical dentin biofilms in vitro. J Endod 2006; 32 (5):434–7.
It has however been argued that antibiotic pastes may Siqueira JF Jr, Rocas IN, Santos SR, et al. Efficacy cause bacterial resistance or allergic reactions. Infact the of instrumentation techniques and irrigation regimens original antibiotic combination used in endodontics in reducing the bacterial population within root (Grossman’s paste which was composed of Penicillin, canals. J Endod 2002; 28 (3):181–4.
Bacitracin, Steptomycin and Nystatin or caprylate Vianna ME, Gomes BP, Berber VB, et al. In vitro sodium) fell out of favor for this reason. Also, minocycline may cause tooth discoloration because of chlorhexidine and sodium hypochlorite. Oral Surg photoactivation. Minocycline binds to calcium ions via Oral Med Oral Pathol Oral Radiol Endod 2004; chelation to form an insoluble complex. It should be limited to the root canal because of the potential risk of Haapasalo HK, Siren EK, Waltimo TM, et al.
tooth discoloration 26. Lenherr et al investigated the Inactivation of local root canal medicaments by discolouration potential of various endodontic materials dentine: an in vitro study. Int Endod J 2000; in bovine tooth model. The most severe discolouration was reported to be detected after 12 months in triple Marending M, Luder HU, Brunner TJ, et al. Effect of antibiotic paste group followed by ledermix paste sodium hypochlorite on human root dentine– indicating the effect of tetracycline 27. A biantibiotic mechanical, chemical and structural evaluation. Int paste, omitting minocycline from the formulation has also been recommended but this mixture does not have the 10. Sim TP, Knowles JC, Ng YL, et al. Effect of sodium antobacterial potency of TAP. Cephalosporins (cefaclor) hypochlorite on mechanical properties of dentine and has also been suggested as an alternative to minocycline tooth surface strain. Int Endod J 2001; 34(2):120–32.
in the triple antibiotic paste 28. Arestin 29 and amoxicilllin 11. Neelakantan P, Sanjeev K, Subbarao CV. Duration- have also been recommended as alternatives to dependent susceptibility of endodontic pathogens to minocycline. However, no clinical trials exist on the calcium hydroxide and chlorhexidene gel used as efficacy of these alternative formulations on the success intracanal medicament: an in vitro evaluation. Oral of revascularization treatment and hence this combination Surg Oral Med Oral Pathol Oral Radiol Endod 2007; can neither be recommended nor refuted at the present 12. Dahlén G, Samuelsson W, Molander A, Reit C.Identification and antimicrobial susceptibility of CONCLUSIONS
enterococci isolated from the root canal. Oral Disinfection of the root canal system is the key to success Microbiol Immunol 2000; 15(5): 309-312.
of revascularization treatment in endodontics. Sodium 13. Doyon GE, Dumsha T, von Fraunhofer JA.Fracture hypochlorite has to be used mandatorily to achieve this resistance of human root dentin exposed to intracanal goal. Disinfection should also be achieved by using calcium hydroxide. J Endod 2005; 31(12): 895-897.
intracanal adjuncts like triple antibiotic paste or 14. Da Silva JM, Silveira A, Santos E, Prado L, Pessoa chorhexidine. Long term clinical trials are needed to evaluate if chlorhexidine gel is as effective as the triple ethylenediaminetetraacetic acid, citric acid and antibiotic paste in revascularization. New combinations phosphoric acid in calcium hydroxide removal from of antibiotics should also be evaluated for successful the root canal: a microscopic cleanliness evaluation.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod2011; 112(6): 820-824.
IJPCR, October-December, 2013, Vol 5, Issue 4, 141-144 Nabeel Ahmed, Prasanna Neelakantan / Antiseptics and Antibiotics… 15. Banchs F, Trope M. Revascularization of immature susceptibility of bacteria taken from infected root permanent teeth with apical periodontitis: new dentine to a mixture of ciprofloxacin, metronidazole treatment protocol? J Endod 2004; 30(4):196–200.
and minocycline. Int Endod J 1996; 29(2):125–130.
16. Mohammadi Z, Abbott PV.The properties and 24. Takushige T, Cruz EV, Asgor Moral A, Hoshino applications of chlorhexidine in endodontics. Int E.Endodontic treatment of primary teeth using a combination of antibacterial drugs. Int Endod J 2004; 17. Gendron R, Grenier D, Sorsa T, Mayrand 25. Bose R, Nummikoski P, Hargreaves K. A metalloproteinases 2, 8, and 9 by chlorhexidine. Clin retrospective evaluation of radiographic outcomes in Diagn Lab Immunol 1999; 6(3): 437-439.
immature teeth with necrotic root canal systems 18. Soares AJ, Lins FF, Nagata JN, Gomes BPFA, Zaia treated with regenerative endodontic procedures. J AA, Ferraz CCR, de Almeida JFA, Souza-Filho FJ.
26. Kim J, Kim Y, Shin S, Park J, Jung I. Tooth Decontamination with Calcium Hydroxide and 2% Chlorhexidine Gel. J Endod 2013; 39(3): 417–420.
associated with triple antibiotic therapy: A case 19. Sato I, Ando-Kurihara N, Kota K, Iwaku M, Hoshino report. J Endod 2010; 36(6):1086–1091.
E. Sterilization of infected root-canal dentine by 27. Lenherr P, Allgayer N, Weiger R, Filippi A, Attin T, topical application of a mixture of ciprofloxacin, Krastl G.Tooth discoloration induced by endodontic metronidazole and minocycline in situ. Int Endod J materials: a laboratory study. Int Endod J 2012; 20. Tripathi KD. Essentials of Medical Pharmacology. 5 28. Thibodeau B, Trope M. Pulp revascularization of a necrotic infected immature permanent tooth: Case 21. Ramamurthy NS, Rifkin BR, Greenwald RA, Xu report and review of the literature. Pediatr Dent JW, Liu Y, Turner G, et al. Inhibition of matrix metalloproteinase-mediated periodontal bone loss in 29. Trope M. Treatment of the immature tooth with a rats: A comparison of 6 chemically modified non-vital pulp and apical periodontitis. Dent Clin tetracyclines. J Periodontol 2002; 73(7): 726–734.
22. Yao JS, Chen Y, Shen F, Young WL, Yang G-Y.
30. Thomson A, Kahler B. Regenerative endodontics-- Comparison of doxycycline and minocycline in the biologically-based treatment for immature permanent inhibition of VEGF-induced smooth muscle cell teeth: a case report and review of the literature. Aust migration. Neurochem Int 2007; 50(3): 524–30.
23. Hoshino E, Kurihara-Aando N, Sato I, Uematsu H, Sato M, Kota K, et al. In-vitro antibacterial IJPCR, October-December, 2013, Vol 5, Issue 4, 141-144
Sarah K. Easley, Ph.D., P.E. Senior Engineer Professional Profile Dr. Sarah Easley is a Senior Engineer in Exponent’s Mechanical Engineering practice. Dr. Easley specializes in solid mechanics, biomechanics, finite element analysis (FEA), and mechanics of materials. Dr. Easley has extensive experience performing numerical analyses of consumer electronics and medical devices. He